Altered lymphocyte profiles and herpes zoster infections in patients with multiple sclerosis on natalizumab.

Cases of herpes zoster (HZ) in patients with MS on natalizumab (NTZ) have been documented. In this study, we assessed lymphocyte subsets in NTZ-treated patients with HZ compared to matched controls without HZ. Twenty unvaccinated patients developed HZ while on NTZ for an incidence rate of 12.3 per 1000 patient-years. These patients had lower CD8+% and higher CD4+:CD8+ ratios (p ⩽ 0.01) than non-HZ matched controls. Two patients with relapsing-remitting MS developed HZ twice while on NTZ. These findings underscore the importance of pre-NTZ HZ vaccination due to potential HZ risk.

Characterization of cortico-meningeal translocator protein expression in multiple sclerosis.

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. PET targeting the 18 kDa mitochondrial translocator protein (TSPO) is a molecular-specific approach to quantifying immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. This study aimed to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratios sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (P = 0.007, by linear regression). Immunohistochemistry, validated using in situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator protein immunostaining was detected on meningeal MHC-class II+ macrophages and cortical-activated MHC-class II+ TMEM119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

Clinical course of multiple sclerosis with comorbid endometriosis: A matched cohort study.

BACKGROUND: Endometriosis (EMS) is pain syndrome in which endometrial tissue grows outside the uterus. EMS is associated with an increased risk of multiple sclerosis (MS), a demyelinating disease of the central nervous system. OBJECTIVE: To characterize clinical phenotypes of a cohort of patients with both EMS and MS compared to a cohort of matched controls with only MS. METHODS: We retrospectively identified patients with EMS and MS at Beth Israel Deaconess Medical Center (BIDMC). We collected data on EMS treatments and analyzed differences in histories of gynecological cancer, smoking, fatigue, anxiety, depression, headache, and neuropathic pain compared to matched controls. We used Wilcoxon signed rank tests for paired samples to compare Expanded Disability Status Scores (EDSS) and timed 25-foot walk values (T25FW). RESULTS: Using a case-control methodology, we found significantly increased EDSS (p < 0.001) and T25FW (p = 0.01) in the EMS-MS group compared to the MS group. More patients in the EMS-MS group had histories of smoking, anxiety, depression, and headaches, while more patients in the MS group had histories of fatigue and neuropathic pain. CONCLUSION: When controlling for age, race, and MS therapy, those with EMS-MS experience more MS disability than controls, suggesting this population requires more monitoring and efficacious treatment.

White matter paramagnetic rim and non-rim lesions share a periventricular gradient in multiple sclerosis: A 7-T imaging study.

BACKGROUND: Paramagnetic rim white matter (WM) lesions (PRL) are thought to be a main driver of non-relapsing multiple sclerosis (MS) progression. It is unknown whether cerebrospinal fluid (CSF)-soluble factors diffusing from the ventricles contribute to PRL formation. OBJECTIVE: To investigate the distribution of PRL and non-rim brain WM lesions as a function of distance from ventricular CSF, their relationship with cortical lesions, the contribution of lesion phenotype, and localization to neurological disability. METHODS: Lesion count and volume of PRL, non-rim WM, leukocortical lesion (LCL), and subpial/intracortical lesions were obtained at 7-T. The brain WM was divided into 1-mm-thick concentric rings radiating from the ventricles to extract PRL and non-rim WM lesion volume from each ring. RESULTS: In total, 61 MS patients with ⩾1 PRL were included in the study. Both PRL and non-rim WM lesion volumes were the highest in the periventricular WM and declined with increasing distance from ventricles. A CSF distance-independent association was found between non-rim WM lesions, PRL, and LCL, but not subpial/intracortical lesions. Periventricular non-rim WM lesion volume was the strongest predictor of neurological disability. CONCLUSIONS: Non-rim and PRL share a gradient of distribution from the ventricles toward the cortex, suggesting that CSF proximity equally impacts the prevalence of both lesion phenotypes.

Bariatric surgery outcomes in multiple sclerosis: Interplay with vitamin D and chronic pain syndromes.

BACKGROUND: Obesity and lower vitamin D levels are associated with adverse outcomes in multiple sclerosis (MS). Bariatric surgery is a safe intervention in patients with MS, although it lowers vitamin D levels in the general population. OBJECTIVE: To investigate the effects of bariatric surgery on vitamin D levels and interrogate risk factors for unsuccessful post-operative weight loss in patients with MS. METHODS: We retrospectively identified patients with MS who underwent bariatric surgery from 2001 to 2023. Wilcoxon signed rank tests for paired samples were used to compare pre- and post-operative body mass index (BMI), expanded disability status scale (EDSS), timed 25-foot walk (T25FW), and median vitamin D values. RESULTS: Following bariatric surgery, patients with MS had a decrease in BMI (mean percent total weight loss of 18.4 %, range 0-38 %, p < 0.001) and an increase in vitamin D values (mean increase of 23 ng/mL, range -4-32 ng/mL, p < 0.001), while no change in EDSS or T25FW was seen. Four out of 20 patients did not lose more than 5 % of their pre-operative BMI, all of whom had chronic pain syndromes and were on gabapentin. CONCLUSION: Healthy vitamin D levels are attainable following bariatric surgery in patients with MS.

High CD4+:CD8+ ratios with herpes zoster infections in patients with multiple sclerosis on dimethyl fumarate.

BACKGROUND: Dimethyl fumarate (DMF) depletes CD8+ and CD4+ T cells, and cases of herpes zoster (HZ) in patients with multiple sclerosis (MS) on DMF have been documented. OBJECTIVES: To evaluate lymphocyte subsets in patients with MS who developed HZ on DMF (Tecfidera) compared to matched controls who did not develop HZ. METHODS: We used linear mixed-effects models to test for differences in white blood cell count, lymphocyte percentage, absolute lymphocyte count, CD3+ percentage, absolute CD3+ count, CD4+ percentage, absolute CD4+ count, CD8+ percentage, absolute CD8+ count, and CD4+:CD8+ ratio over time in HZ and non-HZ groups. RESULTS: Eighteen patients developed HZ while on DMF. The linear mixed-effects model for CD4+:CD8+ ratio showed a significant difference between the HZ and non-HZ groups (p = 0.033). CD4+:CD8+ ratio decreased over time in the HZ group and increased over time in the non-HZ group. CONCLUSION: Patients with MS who develop HZ while on DMF have high CD4+:CD8+ ratios, suggesting an imbalance of CD4+ and CD8+ cells that may put a patient at risk for developing HZ while on DMF. This result emphasizes the need for lymphocyte subset monitoring (including CD4+:CD8+ ratios) on DMF, as well as vaccination prior to DMF initiation.

In vivo characterization of microglia and myelin relation in multiple sclerosis by combined 11C-PBR28 PET and synthetic MRI.

BACKGROUND: The in vivo relation between microglia activation and demyelination in multiple sclerosis is still unclear. OBJECTIVE: We combined 11C-PBR28 positron emission tomography and rapid estimation of myelin for diagnostic imaging (REMyDI) to characterize the relation between these pathological processes in a heterogeneous MS cohort. METHODS: 11C-PBR28 standardized uptake values normalized by a pseudo-reference region (SUVR) were used to measure activated microglia. A voxelwise analysis compared 11C-PBR28 SUVR in the white matter of 38 MS patients and 16 matched healthy controls. The relative difference in SUVR served as a threshold to classify patients' lesioned, perilesional and normal-appearing white matter as active or inactive. REMyDI was acquired in 27 MS patients for assessing myelin content in active and inactive white matter and its relationship with SUVR. Finally, we investigated the contribution of radiological metrics to clinical outcomes. RESULTS: 11C-PBR28 SUVR were abnormally higher in several white matter areas in MS. Myelin content was lower in active compared to inactive corresponding white matter regions. An inverse correlation between SUVR and myelin content was found. Radiological metrics correlated with both neurological and cognitive impairment. CONCLUSION: our data suggest an inverse relation of microglia activation and myelination, particularly in perilesional white matter tissue.

Blunted Post-COVID-19 Humoral Immunity in Patients With CNS Demyelinating Disorders on Anti-CD20 Treatments.

With unclear characteristics of post-infection and post-vaccination immunity, the multiple sclerosis community lacks evidence to guide patients on their continued coronavirus disease 2019 (COVID-19) infection risk. As disease modifying treatments all modulate the immune system, we expect their use to alter acquired immunity to COVID-19, but the specific impact of individual treatments is unclear. To address this, we analyzed the patient and COVID-19 specific characteristics associated with post-infection humoral immunity in 58 patients with central nervous system (CNS) demyelinating disorders in the Boston metropolitan area. Univariate analysis of variance was performed using Mann Whitney U test for continuous variables, and Chi Square or Fisher Exact test for nominal variables. Univariate and stepwise multivariate nominal logistic regression identified clinical characteristics associated with COVID-19 specific nucleocapsid IgG antibody formation post-infection. Our cohort demonstrated a 42% post-infection seropositive rate with a significantly higher rate observed with shorter duration between infection and antibody collection and use of natalizumab over no/other treatment. Use of anti-CD20 treatments compared to no/other treatment was associated with a significantly lower rate of seropositivity. However, only shorter duration between infection and antibody collection as well as use of no/other treatment compared to anti-CD20 treatment were found to be independently associated with increased likelihood of post-infection seropositivity. Additionally, we demonstrate durability of antibody response up to 9 months in a small subset of patients. Thus, our data supports that patients with CNS demyelinating disorders regardless of DMT are able to form a measurable antibody response after COVID-19 infection, and that patients on anti-CD20 treatments form less robust immunity after COVID-19 infection.

Extended B-cell depletion beyond 6-months in patients receiving ocrelizumab or rituximab for CNS demyelinating disease.

OBJECTIVES: To investigate the duration of B-cell depletion in a cohort of patients receiving ocrelizumab or rituximab for multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD). METHODS: We retrospectively searched our database for patients diagnosed with MS or NMOSD, who were receiving ocrelizumab or rituximab and had available CD19 measurements. We collected demographic data, infusion doses, infusion dates, CD19 absolute counts and percentages, and their collection dates. We paired each infusion with the subsequent CD19 measurements recorded before the next infusion, discarding measurements done during a washout period of 30 days after each infusion. We applied three definitions for B-cell depletion, the most stringent of which was an absolute B-cell count ≤20 cells/uL. RESULTS: From 695 patients with demyelinating diseases in our database, over the period of January 1st 2010 to March 1st 2020, we identified 188 patients (178 with MS and 10 with NMOSD), who had received ocrelizumab or rituximab and had available CD19 measurements. 1054 CD19 measurements were captured. B-cell depletion, as defined above, was recorded as far out as 22.8 months after an ocrelizumab infusion, and 22.3 months after a rituximab infusion. Out of 90 B-cell measurements done ≥8 months (>210 days) after ocrelizumab infusion, 45(50%) measurements showed B-cell depletion. Similarly for rituximab, out of 113 measurements, 49(43%) showed B-cell depletion. CONCLUSIONS: This study demonstrates that B-cell depletion after ocrelizumab and rituximab continues beyond the traditional 6-month re-infusion interval in many patients. Our report provides data that can support clinical trials testing increasing the interval of re-infusion with ocrelizumab and rituximab beyond 6-months guided by B-cell measurements.

Cortical and phase rim lesions on 7 T MRI as markers of multiple sclerosis disease progression.

In multiple sclerosis, individual lesion-type patterns on magnetic resonance imaging might be valuable for predicting clinical outcome and monitoring treatment effects. Neuropathological and imaging studies consistently show that cortical lesions contribute to disease progression. The presence of chronic active white matter lesions harbouring a paramagnetic rim on susceptibility-weighted magnetic resonance imaging has also been associated with an aggressive form of multiple sclerosis. It is, however, still uncertain how these two types of lesions relate to each other, or which one plays a greater role in disability progression. In this prospective, longitudinal study in 100 multiple sclerosis patients (74 relapsing-remitting, 26 secondary progressive), we used ultra-high field 7-T susceptibility imaging to characterize cortical and rim lesion presence and evolution. Clinical evaluations were obtained over a mean period of 3.2 years in 71 patients, 46 of which had a follow-up magnetic resonance imaging. At baseline, cortical and rim lesions were identified in 96% and 63% of patients, respectively. Rim lesion prevalence was similar across disease stages. Patients with rim lesions had higher cortical and overall white matter lesion load than subjects without rim lesions (P = 0.018-0.05). Altogether, cortical lesions increased by both count and volume (P = 0.004) over time, while rim lesions expanded their volume (P = 0.023) whilst lacking new rim lesions; rimless white matter lesions increased their count but decreased their volume (P = 0.016). We used a modern machine learning algorithm based on extreme gradient boosting techniques to assess the cumulative power as well as the individual importance of cortical and rim lesion types in predicting disease stage and disability progression, alongside with more traditional imaging markers. The most influential imaging features that discriminated between multiple sclerosis stages (area under the curve±standard deviation = 0.82 ± 0.08) included, as expected, the normalized white matter and thalamic volume, white matter lesion volume, but also leukocortical lesion volume. Subarachnoid cerebrospinal fluid and leukocortical lesion volumes, along with rim lesion volume were the most important predictors of Expanded Disability Status Scale progression (area under the curve±standard deviation = 0.69 ± 0.12). Taken together, these results indicate that while cortical lesions are extremely frequent in multiple sclerosis, rim lesion development occurs only in a subset of patients. Both, however, persist over time and relate to disease progression. Their combined assessment is needed to improve the ability of identifying multiple sclerosis patients at risk of progressing disease.

Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis.

Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T 2 * and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.

A New England COVID-19 Registry of Patients With CNS Demyelinating Disease: A Pilot Analysis.

BACKGROUND AND OBJECTIVES: We sought to define the risk of severe coronavirus disease 2019 (COVID-19) infection requiring hospitalization in patients with CNS demyelinating diseases such as MS and the factors that increase the risk for severe infection to guide decisions regarding patient care during the COVID-19 pandemic. METHODS: A pilot cohort of 91 patients with confirmed or suspected COVID-19 infection from the Northeastern United States was analyzed to characterize patient risk factors and factors associated with an increased severity of COVID-19 infection. Univariate analysis of variance was performed using the Mann-Whitney U test or analysis of variance for continuous variables and the χ2 or Fisher exact test for nominal variables. Univariate and stepwise multivariate logistic regression identified clinical characteristics or symptoms associated with hospitalization. RESULTS: Our cohort demonstrated a 27.5% hospitalization rate and a 4.4% case fatality rate. Performance on Timed 25-Foot Walk before COVID-19 infection, age, number of comorbidities, and presenting symptoms of nausea/vomiting and neurologic symptoms (e.g., paresthesia or weakness) were independent risk factors for hospitalization, whereas headache predicted a milder course without hospitalization. An absolute lymphocyte count was lower in hospitalized patients during COVID-19 infection. Use of disease-modifying therapy did not increase the risk of hospitalization but was associated with an increased need for respiratory support. DISCUSSION: The case fatality and hospitalization rates in our cohort were similar to those found in MS and general population COVID-19 cohorts within the region. Hospitalization was associated with increased disability, age, and comorbidities but not disease-modifying therapy use.

Prevalence of Latent Tuberculosis in the Multiple Sclerosis Clinic and Effect of Multiple Sclerosis Treatment on Tuberculosis Testing.

BACKGROUND: Patients with a compromised immune system are at risk for converting from latent tuberculosis infection (LTBI) to active tuberculosis (TB) infection. Multiple sclerosis (MS) therapies may put individuals with LTBI at higher risk of TB. METHODS: Patients at the Beth Israel Deaconess Medical Center MS Clinic were screened for TB as part of routine testing with the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Ltd) from 2013 to 2017. Patients were tested either before or during immunomodulatory therapy. RESULTS: Four of 222 patients (1.8%; 95% CI, 0.1%-3.6%) had positive QFT-GIT results; three patients had risk factors for TB, having emigrated from TB-endemic countries or worked in the health care industry. Twenty-eight of 222 patients (12.6%) had an indeterminate assay result, and 75.0% of these occurred in patients taking dimethyl fumarate. Fingolimod, natalizumab, or anti-CD20 treatments showed 0% to 7.7% indeterminate results. CONCLUSIONS: The prevalence of LTBI was 1.8% in the Beth Israel Deaconess Medical Center MS Clinic. Not all LTBI cases were associated with known risk factors for TB. Screening for LTBI before starting immunosuppressive agents for MS could help prevent activation of TB. Dimethyl fumarate use is associated with indeterminate QFT-GIT results, possibly due to functional effects on lymphocytes and levels of cytokines, such as interferon gamma. In contrast, fingolimod use was rarely associated with indeterminate QFT-GIT results despite a high rate of lymphopenia in virtually all patients.

CLICK-MS and MASTER-2 Phase IV trial design: cladribine tablets in suboptimally controlled relapsing multiple sclerosis.

Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine tablets are limited. CLICK-MS and MASTER-2 are single arm, observational, 30-month, Phase IV studies in the US evaluating the effectiveness and safety of cladribine tablets 3.5 mg/kg in patients with relapsing-remitting MS or active secondary progressive MS who had suboptimal response to prior injectable (CLICK-MS), or infusion/oral (MASTER-2) disease-modifying therapy. The primary end point is 24-month annualized relapse rate. Key secondary end points include patient-reported outcomes on quality of life measures, treatment adherence and adverse events. Studies began in 2019 and are expected to be completed in 2023. Trial registration number • CLICK-MS: NCT03933215 (ClinicalTrials.gov) Full title; CLadribine tablets: observational evaluation of effectIveness and patient-reported outcomes in suboptimally Controlled patients previously taKing injectable disease-modifying drugs for relapsing forms of Multiple Sclerosis • MASTER-2: NCT03933202 (ClinicalTrials.gov) Full title; Cladribine tablets: observational evaluation of effectiveness and patient-reported outcomes in suboptiMAlly controlled patientS previously Taking oral or infusion disEase-modifying dRugs for relapsing forms of multiple sclerosis.

The relevance of multiple sclerosis cortical lesions on cortical thinning and their clinical impact as assessed by 7.0-T MRI.

OBJECTIVE: This study aimed to investigate at 7.0-T MRI a) the role of multiple sclerosis (MS) cortical lesions in cortical tissue loss b) their relation to neurological disability. METHODS: In 76 relapsing remitting and 26 secondary progressive MS patients (N = 102) and 56 healthy subjects 7.0-T T2*-weighted images were acquired for lesion segmentation; 3.0-T T1-weighted structural scans for cortical surface reconstruction/cortical thickness estimation. Patients were dichotomized based on the median cortical lesion volume in low and high cortical lesion load groups that differed by age, MS phenotype and degree of neurological disability. Group differences in cortical thickness were tested on reconstructed cortical surface. Patients were evaluated clinically by means of the Expanded Disability Status Scale (EDSS). RESULTS: Cortical lesions were detected in 96% of patients. White matter lesion load was greater in the high than in the low cortical lesion load MS group (p = 0.01). Both MS groups disclosed clusters (prevalently parietal) of cortical thinning relative to healthy subjects, though these regions did not show the highest cortical lesion density, which predominantly involved frontal regions. Cortical thickness decreased on average by 0.37 mm, (p = 0.002) in MS patients for each unit standard deviation change in white matter lesion volume. The odds of having a higher EDSS were associated with cortical lesion volume (1.78, p = 0.01) and disease duration (1.15, p < 0.001). CONCLUSION: Cortical thinning in MS is not directly related to cortical lesion load but rather with white matter lesion volume. Neurological disability in MS is better explained by cortical lesion volume assessment.

Unilateral Relapsing Primary Angiitis of the CNS: An Entity Suggesting Differences in the Immune Response Between the Cerebral Hemispheres.

OBJECTIVE: To determine whether studying patients with strictly unilateral relapsing primary angiitis of the CNS (UR-PACNS) can support hemispheric differences in immune response mechanisms, we reviewed characteristics of a group of such patients. METHODS: We surveiled our institution for patients with UR-PACNS, after characterizing one such case. We defined UR-PACNS as PACNS with clinical and radiographic relapses strictly recurring in 1 brain hemisphere, with or without hemiatrophy. PACNS must have been biopsy proven. Three total cases were identified at our institution. A literature search for similar reports yielded 4 additional cases. The combined 7 cases were reviewed for demographic, clinical, imaging, and pathologic trends. RESULTS: The median age at time of clinical onset among the 7 cases was 26 years (range 10-49 years); 5 were male (71%). All 7 patients presented with seizures. The mean follow-up duration was 7.5 years (4-14.1 years). The annualized relapse rate ranged between 0.2 and 1. UR-PACNS involved the left cerebral hemisphere in 5 of the 7 patients. There was no consistent relationship between the patient's dominant hand and the diseased side. When performed (5 cases), conventional angiogram was nondiagnostic. CSF examination showed nucleated cells and protein levels in normal range in 3 cases and ranged from 6 to 11 cells/µL and 49 to 110 mg/dL in 4 cases, respectively. All cases were diagnosed with lesional biopsy, showing lymphocytic type of vasculitis of the small- and medium-sized vessels. Patients treated with steroids alone showed progression. Induction therapy with cyclophosphamide or rituximab followed by a steroid sparing agent resulted in the most consistent disease remission. CONCLUSIONS: Combining our 3 cases with others reported in the literature allows better clinical understanding about this rare and extremely puzzling disease entity. We hypothesize that a functional difference in immune responses, caused by such discrepancies as basal levels of cytokines, asymmetric distribution of microglia, and differences in modulation of the systemic immune functions, rather than a structural antigenic difference, between the right and left brain may explain this phenomenon, but this is speculative.

Characterization of thalamic lesions and their correlates in multiple sclerosis by ultra-high-field MRI.

BACKGROUND: Thalamic pathology is a marker for neurodegeneration and multiple sclerosis (MS) disease progression. OBJECTIVE: To characterize (1) the morphology of thalamic lesions, (2) their relation to cortical and white matter (WM) lesions, and (3) clinical measures, and to assess (4) the imaging correlates of thalamic atrophy. METHODS: A total of 90 MS patients and 44 healthy controls underwent acquisition of 7 Tesla images for lesion segmentation and 3 Tesla scans for atrophy evaluation. Thalamic lesions were classified according to the shape and the presence of a central venule. Regression analysis identified the predictors of (1) thalamic atrophy, (2) neurological disability, and (3) information processing speed. RESULTS: Thalamic lesions were mostly ovoid than periventricular, and for the great majority (78%) displayed a central venule. Lesion volume in the thalamus, cortex, and WM did not correlate with each other. Thalamic atrophy was only associated with WM lesion volume (p = 0.002); subpial and WM lesion volumes were associated with neurological disability (p = 0.016; p < 0.001); and WM and thalamic lesion volumes were related with cognitive impairment (p < 0.001; p = 0.03). CONCLUSION: Thalamic lesions are unrelated to those in the cortex and WM, suggesting that they may not share common pathogenic mechanisms and do not contribute to thalamic atrophy. Combined WM, subpial, and thalamic lesion volumes at 7 Tesla contribute to the disease severity.

Brainstem lesions are associated with sleep apnea in multiple sclerosis.

BACKGROUND: Studies linking MRI findings in MS patients with obstructive sleep apnea severity are limited. OBJECTIVE: We conducted a retrospective study to assess MRI abnormalities associated with obstructive sleep apnea (OSA) in patients with multiple sclerosis (MS). METHODS: We performed retrospective chart review of 65 patients with multiple sclerosis who had undergone polysomnography (PSG) for fatigue as well as brain MRI. We measured the number of lesions in the brainstem and calculated the standardized third ventricular width (sTVW) as a measure of brain atrophy, and subsequently performed correlation analyses of the apnea-hypopnea index (AHI) with brainstem lesion location, sTVW, and Expanded Disability Status Scale (EDSS). RESULTS: MS Patients with OSA were significantly older and had a higher body mass index (BMI) and higher AHI measures than patients without OSA. After adjustment for covariates, significant associations were found between AHI and lesion burden in the midbrain (p < 0.01) and pons (p = 0.05), but not medulla. CONCLUSIONS: Midbrain and pontine lesions burden correlated with AHI, suggesting MS lesion location could contribute to development of OSA.

7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis.

We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.

Leptomeningeal Enhancement on 3D-FLAIR MRI in Multiple Sclerosis: Systematic Observations in Clinical Practice.

BACKGROUND AND PURPOSE: Meningeal inflammation is implicated in cortical demyelination and disability progression in multiple sclerosis (MS). Gadolinium (Gd)-enhanced 3-dimensional (3D) FLAIR (fluid-attenuated inversion recovery) magnetic resonance imaging (MRI) can identify leptomeningeal enhancement (LME) in MS. Further characterization is needed to determine if LME is an imaging biomarker for meningeal inflammation. We sought to characterize the natural history of LME in the community setting, including persistence/resolution, effect of disease-modifying therapy, scanner variability, timing of acquisition, and imaging pitfalls that may lead to misinterpretation. METHODS: A total of 341 MRI exams with Gd-enhanced 3D-FLAIR were reviewed in MS and non-MS patients to determine frequency of enhancement by MS subtype and association with therapy. A phantom was used to assess scanner variability. Two MS patients with seven LME were imaged at four postinjection time points to generate time-intensity curves. Imaging pitfalls were compiled. RESULTS: A total of 16.6% (40/241) of MS patients revealed LME compared to 8% (8/100) in non-MS patients (P = .04). There was no association with MS subtype, therapy, or disease activity. Detection using General Electric's version of 3D-FLAIR (29%) was greater than with Siemen's 3D-FLAIR (12%) at 1.5T (Tesla) (P < .001). Lesions were generally stable but resolved in 2 patients following high-dose steroids. LME kinetics were heterogeneous, even within patients, without uniform optimal time for acquisition. Enhancement curves exhibited three different variations, similar to the two-compartment model. Imaging pitfalls included enhancements of uncertain biologic significance, cortical veins and anatomic structures, and imaging artifacts. CONCLUSIONS: Awareness of LME characteristics, variability with imaging parameters, and imaging pitfalls will facilitate determining the potential role as an imaging biomarker for meningeal inflammation.